Process for producing chloromethylphenylacetic acid

ABSTRACT

A method for preparing chloromethylphenylacetic acids represented by formula (II):wherein a methylphenylacetic acid represented by formula (I):is reacted with a chlorine gas, in an inert solvent, under the irradiation with light or in the presence of a radical initiator, is disclosed. According to the preparation method, high purity chloromethylphenylacetic acids can be prepared at a high yield, without using toxic sulfuryl chloride as a chlorinating agent, by chlorinating the methyl group of the methylphenylacetic acids at a high selectivity while suppressing by-production of a dichloro form or alpha-chloro form.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/JP99/02125 which has an Internationalfiling date of Apr. 21, 1999, which designated the United States ofAmerica.

TECHNICAL FIELD

The present invention relates to a method for preparingchloromethylphenylacetic acids, and more specifically to a method forpreparing chloromethylphenylacetic acids at a high selectivity and ahigh yield, without using sulfuryl chloride as a chlorinating agent.

BACKGROUND ART

Chloromethylphenylacetic acids are compounds useful as raw materials andintermediate products for pharmaceuticals, agricultural chemicals, andthe like.

One known conventional method for preparing chloromethylphenylaceticacids is a method for preparing 2-halomethylphenylacetic acids by aring-opening reaction of 3-isochromanone with hydrogen halide, asdescribed in the reference example of JP-A-54-138536 (“JP-A” meansunexamined published Japanese patent application). However3-isochromanone as the starting material in this method is expensive,and there is a problem in view of the production cost.

Further, a method of obtaining 2-chloromethylphenylacetic acids byreacting, in carbon tetrachloride, 2-methyl phenylacetic acid withbromine, in the presence of 2,2′-azobisisobutyronitrile (AIBN), underirradiation with ultraviolet rays, to form 2-bromomethyl phenylaceticacids, and then reacting the 2-bromomethyl phenylacetic acids withlithium chloride, is reported in J. CHEM. SOC., CHEM. COMMUN., 1993, p.399. However, this method is not preferred for industrial practice,since it involves a number of steps and the overall yield is as low as54%.

Further, WO97/48692 reports a method of reacting 2-methyl phenylaceticacids with sulfuryl chloride, in the presence of a radical initiator, toobtain 2-chloromethylphenylacetic acid. However, the yield is 62.15% andthe purity is 95.7%, with regard to the 2-chloromethylphenylacetic acidsobtained by this method, which is not yet industrially satisfactory. Inaddition, sulfuryl chloride used in this method is toxic, and further,gaseous sulfurous acid formed by the reaction is highly toxic andcorrosive, and the concentration of gaseous sulfurous acid in exhaustgases is strictly regulated, involving such problems mentioned above forindustrial practice.

Accordingly, an object of the present invention is to provide a methodcapable of preparing chloromethylphenylacetic acids at a high yield anda high selectivity, without using sulfuryl chloride as the chlorinatingagent.

Other and further objects, features, and advantages of the inventionwill appear more fully from the following description.

DISCLOSURE OF INVENTION

The present inventors have made earnest studies for solving theforegoing subject, and as a result, found that aimedchloromethylphenylacetic acids can be obtained at a high yield byreacting methyl phenylacetic acids and a chlorine gas, in an inertsolvent, under the irradiation with light or in the presence of aradical initiator, to chlorinate only the methyl group at a highselectivity. The present inventors have accomplished the presentinvention based on the finding.

That is, the present invention provides:

(1) a method for preparing chloromethylphenylacetic acids represented byformula (II):

 wherein a methyl phenylacetic acid represented by formula (I):

 is reacted with a chlorine gas, in an inert solvent, under theirradiation with light or in the presence of a radical initiator,

(2) a method for preparing chloromethylphenylacetic acids as describedin (1), wherein the reaction temperature is 70° C. or lower, and

(3) a method for preparing chloromethylphenylacetic acids as describedin (1) or (2), wherein the inert solvent is at least one selected frommonochlorobenzene, dichlorobenzenes, trichlorobenzenes, fluorobenzenes,trifluoromethylbenzenes, bistrifluoromethylbenzenes orchlorotrifluoromethylbenzenes.

BEST MODE FOR CARRYING OUT THE INVENTION

The methyl phenylacetic acid used as the starting raw material in thepresent invention is represented by the formula (I), and specificallyone of 2-methyl phenylacetic acid, 3-methyl phenylacetic acid or4-methyl phenylacetic acid, or a mixture of two or more of them.

The chloromethylphenylacetic acid obtained in the present invention isrepresented by the formula (II), and is one of2-chloromethylphenylacetic acid, 3-chloromethylphenylacetic acid or4-chloromethylphenylacetic acid, or a mixture of two or more of them,corresponding to the starting raw materials described above.

In the present invention, the chlorine gas is used as the chlorinatingagent and the amount to be used is preferably from 0.2 to 2 mol, andmore preferably from 0.8 to 1.2 mol, based on one mol of the methylphenylacetic acid represented by the formula (I).

In the method of the present invention, the compound represented by theformula (I) and the chlorine gas are reacted under the irradiation withlight or in the presence of a radical initiator. There is no particularrestriction on the method of light irradiation and light including anultraviolet region can be used preferably. For example, it can becarried out by using a mercury lamp or the like as a light source. Alsofor the radical initiator, those used generally can be used with noparticular restriction. Specifically, benzoyl peroxide,2,2′-azobisisobutyronitrile can be mentioned for example. The amount ofthe radical initiator to be used is generally from 0.005 to 0.1 mol,based on one mol of the compound represented by the formula (I).

The inert solvent usable in the present invention is a halogenatedhydrocarbon, preferably, an aryl halide (for example, benzene halide),and there is no particular restriction so long as it can generally beused as the inert solvent for radial chlorinating reaction. Aryl halideincludes those halogenated on the side chain. As specific examples ofsuch inert solvent, one of monochlorobenzene, dichlorobenzenes,trichlorobenzenes, fluorobenzenes, trifluoromethylbenzenes,bistrifluoromethylbenzenes or chlorotrifluoromethylbenzenes, or a mixedsolvent of two or more of them, can be used. It is, more preferably, atleast one selected from monochlorobenzene, o-dichlorobenzene or4-chlorotrifluoromethylbenzene.

There is no particular restriction on the amount of the solvent to beused in the present invention and it is preferably from 0.05 to 10liter, and more preferably from 0.2 to 3 liter, based on one mol of thecompound represented by the formula (I) in the industrial practice.

The chlorinating reaction in the present invention can be conducted at atemperature, preferably in the range of 70° C. or lower, and morepreferably from 20 to 50° C.

Chloromethylphenylacetic acids at a high purity can be obtained easilyat a high yield, by cooling the reaction solution after the completionof the reaction and then filtering and separating the precipitateddesired compound from the reaction system. With an aim of furtherimproving the purity, the obtained compound may be purified byrecrystallization or the like.

According to the present invention, high purity chloromethylphenylaceticacids can be prepared at a high yield, without using toxic sulfurylchlorides as a chlorinating agent, by chlorinating the methyl group ofthe methyl phenylacetic acids at a high selectivity while suppressingby-production of dichloro form or α-chloro form. In the method of thepresent invention, since reaction conditions are mild and the number ofsteps is reduced, it can be practiced industrially at a reducedproduction cost. 2-chloromethylphenylacetic acids prepared by thepresent invention can also be converted easily into 3-isochromanone,which is used as intermediate products for medicines and agriculturalagents, by treating with a base by the known method (Zh. Org. Khim[1973] 9 (10) 2145).

EXAMPLES

Now, the present invention is described in more detail based on thefollowing examples, which do not limit the invention.

Example 1

30 g of 2-methyl phenylacetic acid and 60 g of monochlorobenzene werecharged to a 100 ml flask equipped with a gas blowing tube, a refluxcondenser and a stirrer, and reaction was initiated under theirradiation with ultraviolet rays by a mercury lamp while controllingthe reaction temperature to 45° C. and blowing a chlorine gas. Thechlorine gas was supplied by 19 g for 8 hours.

When reaction solution after the completion of the reaction was analyzedon gas chromatography, 2-methyl phenylacetic acid as the raw material,2-chloromethylphenylacetic acid, the desired compound, and2-methyl-α-chlorophenylacetic acid, 2-dichloromethylphenylacetic acid,2-chloromethyl-α-chlorophenylacetic acid as by-products were presenteach at the ratio shown in Table 1. The selectivity to2-chloromethylphenylacetic acid (ratio of 2-chloromethylphenylaceticacid in the products) was 88.7%.

After the completion of the reaction, the reaction solution was cooledto 20° C., and precipitates were filtered and separated to obtain 26.6 gof 2-chloromehtyl phenylacetic acid (purity: 98.5%, yield: 72%).

Examples 2 to 4

2-chloromethylphenylacetic acid was prepared in the same manner as inExample 1 except for using the solvents shown in Table 1 instead ofmonochlorobenzene. When the reaction solution after the completion ofthe reaction was analyzed on gas chromatography, each of the compoundswas present at the ratio shown in Table 1. The selectivity to2-chloromethylphenylacetic acid is also shown in Table 1.

Examples 5 to 8

2-chloromethylphenylacetic acid was prepared in the same manner as inExample 1 except for changing the reaction temperature and/or amount ofsolvent as shown in Table 1. When the reaction solution after thecompletion of the reaction was analyzed on gas chromatography, each ofthe compounds was present at the ratio shown in Table 1. The selectivityto 2-chloromethylphenylacetic acid is also shown in Table 1.

Example 9

4-chloromethylphenylacetic acid was prepared in the same manner as inExample 1 except for using 30 g of 4-methyl phenylacetic acid instead of2-methyl phenylacetic acid and using 90 g of monochlorobenzene.

When reaction solution after the completion of the reaction was analyzedon gas chromatography, 6.8% of 4-methyl phenylacetic acid as the rawmaterial, 74.8% of 4-chloromethylphenylacetic acid, the desiredcompound, and 0.5% of 4-methyl-α-chlorophenylacetic acid, 5.8% of4-dichloromethylphenylacetic acid and 7.7% of4-chloromethyl-α-chlorophenylacetic acid, as by-products, were present.The selectivity to 4-chloromethylphenylacetic acid was 80.2%.

After the completion of the reaction, the reaction solution was cooledto 20° C., and precipitates were filtered and separated to obtain 26.2 gof 4-chloromehtyl phenylacetic acid (purity: 96.4%, yield: 71%).

Comparative Example 1

30 g of 2-methyl phenylacetic acid, 60 g of monochlorobenzene and2,2′-azobisisobutyronitrile as a radical initiator were charged to a 200ml flask equipped with a reflux condenser, a stirrer and a thermometer,and the reaction temperature was controlled to 70° C. and 29.7 g ofsulfuryl chloride was added dropwise thereto for 5 hours.

When the reaction solution after the completion of the reaction wasanalyzed on gas chromatography, each of the compounds was present at theratio shown in Table 1. The selectivity to 2-chloromethylphenylaceticacid was 75.4%.

After the completion of the reaction, the reaction solution was cooledto 20° C., and precipitates were filtered and separated to obtain 23.0 gof 2-chloromehtyl phenylacetic acid (purity: 96.8%, yield: 62%).

Reference Example 1

2-chloromethylphenylacetic acid was prepared in the same manner as inExample 1 except for changing the reaction temperature to 80° C. Whenthe reaction solution after the completion of the reaction was analyzedon gas chromatography, each of the compounds was present at the ratioshown in Table 1. The selectivity to 2-chloromethylphenylacetic acid was70.0%.

TABLE 1 Reac- Amount tion GC composition of Chroli- tempera- (area %)Selec- solvent nating ture α-Cl α-Cl tivity*⁶ No. Solvent (g) agent (°C.) OMPA*¹ 2CMPA*² OMPA*³ 2DCMPA*⁴ CMPA*⁵ (%) Example 1monochlorobenzene 60 chlorine 45 4.5 84.7 1.4 3.9 4.4 88.7 gas 2o-dichlorobenzene 75 chlorine 45 5.0 81.6 1.5 5.2 5.4 85.9 gas 31,3-bistrifluoro 60 chlorine 45 19.8 70.7 0.9 2.0 3.8 88.1 methylbenzenegas 4 4-chlorotrifluoro 120 chlorine 45 5.7 81.9 1.0 4.3 5.5 86.8methylbenzene gas 5 monochlorobenzene 60 chlorine 60 8.5 75.4 2.6 7.05.8 82.4 gas 6 monochlorobenzene 240 chlorine 20 5.2 83.1 1.6 4.5 3.687.7 gas 7 monochlorobenzene 60 chlorine 20 6.7 84.5 0.1 3.4 4.2 90.6gas 8 monochlorobenzene 60 chlorine 5 3.0 86.7 0.2 2.1 3.7 89.4 gasComparative   1*⁷ monochlorobenzene 60 sulfuryl 70 6.6 70.4 2.5 11.3 8.875.4 Example chloride Reference 1 monochlorobenzene 60 chlorine 80 2.268.5 1.7 12.0 9.4 70.0 Example gas (note) *¹OMPA: 2-methylphenylaceticacid *²2CMPA: 2-chloromethylphenylacetic acid *³α-ClOMPA:2-methyl-α-chlorophenylacetic acid *⁴2DCMPA:2-dichloromethylphenylacetic acid *⁵α-ClCMPA:2-chloromethyl-α-chlorophenylacetic acid *⁶Selectivity (ratio of 2CMPAin product) (%) = 100 × [2CMPA/(100 − OMPA)] *⁷2,2′-azobisisonitrile wasused instead of mercury lamp irradiation

INDUSTRIAL APPLICABILITY

The preparation method according to the present invention is suitable asa method for preparing high purity chloromethylphenylacetic acids at ahigh yield, without using toxic sulfuryl chloride as a chlorinatingagent, by chlorinating the methyl group of methyl phenylacetic acid at ahigh selectivity while suppressing by-production of dichloro form orα-chloro form. The method of the present invention can be practicedindustrially at a reduced production cost since the reaction conditionsare mild and the number of steps is reduced. Further,2-chloromethylphenylacetic acid prepared by the method of the presentinvention can also be converted easily into 3-isochromanone by treatingwith a base by a known method, which can be used as intermediateproducts for medicines and agricultural chemicals.

Having described our invention as related to the present embodiments, itis our intention that the invention not be limited by any of the detailsof the description, unless otherwise specified, but rather be construedbroadly within its spirit and scope as set out in the accompanyingclaims.

What is claimed is:
 1. A method for preparing chloromethylphenylaceticacids represented by formula (II):

wherein a methylphenylacetic acid represented by formula (I):

is reacted with a chlorine gas, in an inert solvent, under theirradiation with light or in the presence of a radical initiator.
 2. Themethod for preparing chloromethylphenylacetic acids as claimed in claim1, wherein the reaction temperature is 70° C. or lower.
 3. The methodfor preparing chloromethylphenylacetic acids as claimed in claim 2,wherein the reaction temperature is in a range of from 20 to 50° C. 4.The method for preparing chloromethylphenylacetic acids as claimed inclaim 1, wherein the inert solvent is at least one selected frommonochlorobenzene, dichlorobenzenes, trichlorobenzenes, fluorobenzenes,trifluoromethylbenzenes, bistrifluoromethylbenzenes orchlorotrifluoromethylbenzenes.
 5. The method for preparingchloromethylphenylacetic acids as claimed in claim 4, wherein the inertsolvent is at least one selected from monochlorobenzene,o-dichlorobenzene or 4-chlorotrifluoromethylbenzene.
 6. The method forpreparing chloromethylphenylacetic acids as claimed in claim 1, whereinfrom 0.2 to 2 mol of the chlorine gas is reacted with one mol ofmethylphenylacetic acids represented by the formula (I).
 7. The methodfor preparing chloromethylphenylacetic acids as claimed in claim 1,wherein the reaction is carried out under the irradiation with light andthe light irradiation is conducted with light including an ultravioletregion.
 8. The method for preparing chloromethylphenylacetic acids asclaimed in claim 1, wherein the reaction is carried out in the presenceof the radical initiator and the radical initiator is benzoyl peroxideor 2,2′-azobisisobutyronitrile.
 9. The method for preparingchloromethylphenylacetic acids as claimed in claim 1, wherein thereaction is carried out in the presence of a radical initiator and theamount of the radical initiator to be used is from 0.005 to 0.1 molbased on one mol of the compound represented by the formula (I).
 10. Themethod for preparing chloromethylphenylacetic acids as claimed in claim1, wherein from 0.05 to 10 liter of the inert solvent is used based onone mol of the compound represented by the formula (I).